Lotronex ® (alosetron HCl) Tablets Risk-Benefit Issues

1. Lotronex® (alosetron HCl) TabletsRisk-Benefit Issues Victor F. C. Raczkowski, M.D. Director, Division of Gastrointestinal and Coagulation Drug Products April 23, 2002

2. Modifying the Benefit-Risk Balance • Three principal approaches • Limit use to patients with most disabling IBS symptoms • Increase benefit • Decrease risk

3. Limiting Lotronex Use to PatientsWith the Most Disabling Symptoms • Burden of illness is variable in patients with IBS • Symptoms: relatively minor  disabling • Patients with most disabling symptoms: • Stand to benefit the most • May accept greater risk

4. Increase Benefit • Lotronex has effects on several symptoms of IBS (e.g., diarrhea, urgency, abdominal pain and discomfort) • Some patients with severe symptoms (e.g., urgency) have large benefit • Patients with harder stools and stool frequency <2/day appear to have less benefit

5. Increase Benefit • Quality-of-life assessments suggest Lotronex may improve functional performance • But marked improvements in functional performance could be better assessed in a randomized withdrawal study of IBS patients with disabling symptoms

6. Decrease Risk • Avoid adverse events, if possible • Appropriate patient selection and education • Appropriate physician selection and education • Modify drug exposure • Consider relevant IBS factors • Manage adverse events

7. Two Goals of Patient Selection • Prescribe only to patients in whom the benefits exceed the risks • Appropriate inclusion criteria • Appropriate exclusion criteria • Adequate disclaimers • Prescribe only to adequately informed patients

8. How Best to DescribePatients in Whom Benefits Exceed Risks? • Approved Indication: February 2000 • Revised Indication: August 2000 • Proposed Indication: April 2002

9. Approved Indication (February 2000) • Lotronex is indicated for the treatment of irritable bowel syndrome (IBS) in women whose predominant bowel symptom is diarrhea. • The safety and effectiveness of Lotronex in men have not been established.

10. Revised Indication (August 2000) • Lotronex is indicated for the treatment of women with diarrhea-predominant irritable bowel syndrome (IBS). Diarrhea-predominant IBS is characterized by at least 3 months of recurrent or continuous symptoms of abdominal pain or discomfort with either urgency, an increase in frequency of stool, or diarrhea not attributable to organic disease (see Appendix). • Use in men: similar to original labeling.

11. Proposed Indication (April 2002) • Lotronex is indicated only for women with diarrhea-predominant irritable bowel syndrome (IBS) who have failed to respond to conventional therapy and who have signed the Patient-Physician Agreement (see BOXED WARNING, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). • Use in men: similar to original labeling.

12. Does the Proposed Plan Adequately Describe Appropriate Patients? • Appropriate Inclusion Criteria? • Severity of IBS symptoms • Degree of disability from IBS • Chronicity of IBS • Failure of conventional IBS therapies • Other important characteristics

13. Does the Proposed Plan Adequately Describe Appropriate Patients? • Appropriate Exclusion Criteria? • Contraindications • Patients less likely to benefit • Patients with risk factors (if known) • Special populations (e.g., men)? • Should the Patient-Physician Agreement include these elements for self-attestation?

14. Proposed Risk-Management Plan:Informing Patients • Sign Patient-Physician Agreement • Agreement filed in medical record • Receive Medication Guide • Professional labeling: Physicians instructed to counsel patients on risks and benefits • Slone-Eckerd survey will assess patient knowledge

15. Goals of Physician Selection • Lotronex prescribed only by physicians: • knowledgeable and experienced in diagnosis and treatment of IBS • able to diagnose and manage ischemic colitis and complications of constipation • knowledgeable about Lotronex

16. Does the Proposed Plan Adequately Describe Appropriate Physicians? • Knowledge • Experience • Specialty • Other important characteristics

17. Does the Proposed Labeling Adequately Describe Appropriate Physicians? • Physicians self attest to qualifications • Sign Patient-Physician Agreement • Agreement filed in patient’s medical record • Physicians’ agreements are not audited • Utilization study of UnitedHealthcare to assess physician-prescribing behavior

18. Potentially SeriousDrug-Associated Adverse Events • Constipation (dose-related) • Ischemic colitis (idiosyncratic?) • Small-bowel ischemia (idiosyncratic?)

19. Modify Drug Exposure • Limit dosage to decrease dosage-related side effects: • Starting therapy (titrate upward) • Adjust dose during maintenance therapy? • Drug holidays? • Discontinue therapy in non-responders • Continue therapy only in true responders (versus apparent responders)?

20. Consider Relevant IBS Factors • IBS waxes and wanes • Greater risk of adverse events during particular phases of condition? • Lotronex should not be used in patients with constipation

21. Manage Adverse Events • Identify and act on early warning signs • Patient education • Patient-Physician Agreement • Medication Guide • Physician education • Professional labeling • Patient-Physician Agreement • Monitoring of patients

22. Conclusions:Patient Selection • Burden of illness is variable in patients with IBS • Lotronex has beneficial effects on several symptoms of IBS • Patients with most disabling symptoms stand to benefit the most from Lotronex • Risk-benefit balance is most favorable in patients with most disabling symptoms.

23. Conclusions:Safety Outcomes • Lotronex is associated with serious, or potentially serious, adverse events such as complications of constipation, ischemic colitis, mesenteric ischemia, and death • Outcomes of ischemic colitis and constipation vary in seriousness • Presenting symptoms do not necessarily predict severity of outcome

24. Conclusions:Ischemic Colitis • Risk factors for ischemic colitis or mesenteric ischemia have not been identified • Cumulative risk of ischemic colitis increases over time (~2-5/1000 at 3 months) • Risk may decrease after 1 month, little information after 6 months

25. Conclusions:Constipation • Constipation is a frequent, dose-related side effect associated with Lotronex • ~25-30% experience constipation with Lotronex at 1 mg twice daily • ~10% withdrew from clinical trials because of constipation at 1 mg twice daily • Some adverse outcomes of constipation are serious

26. Conclusions:Risk-Management Plan • Full range of drug access options should be considered • Could begin with a more restrictive plan • Program monitoring should occur at • level of the patient • level of the physician • level of the pharmacist

27. Conclusions:Risk-Management Plan • Success of the plan could be evaluated through: • Process controls • Evaluation of outcomes